In certain aspects, the present invention relates to compositions including a class of benzodiazepine derivatives that are subunit-selective GABAA receptor agonists. Such compositions are useful for the treatment of neuropathic pain, migraine related pain and inflammatory pain, with reduced sedative, hypnotic, and ataxic side effects. In other aspects, the present invention relates to methods of treatment or prevention of neuropathic pain, migraine related pain and inflammatory pain, using such benzodiazepine derivatives that are subunit-selective GABAA receptor agonists.
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. Pain usually results from activation of nociceptive afferents (pain receptors) by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as “pains resulting from disease or damage of the peripheral or central nervous systems, and from dysfunction of the nervous system.”
Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia, nerve injuries after surgery, pain following paraplegia, hypersensitivity to non-painful stimuli (allodynia), e.g. after surgery or during migraine attacks, spontaneous pain, hyperalgesia, diffuse muscle tenderness of myofacial syndromes, sensory abnormalities of the gastrointestinal tract, e.g. in irritable bowel disease, or chest pain and a large proportion of back pain. Cancer pain and AIDS-associated pain also qualify as neuropathic pain. The most commonly prescribed drugs for the treatment of pain include tricyclic antidepressants, anti-epileptic drugs, opioid analgesics and, in case of local pain, cream and patches delivering analgesics. These analgesics are of limited use in the treatment of neuropathic pain. Currently prescribed drugs for neuropathic pain are not effective for all patients, have various side effects and frequently provide only modest pain relief. Accordingly, there is a significant unmet medical need for drugs to specifically treat neuropathic pain.
Inflammatory pain is triggered by nerve endings that become irritated when surrounded by inflamed tissue. Inflammatory pain is most commonly associated with conditions such as trauma, osteoarthritis, rheumatoid arthritis, post surgery recovery and some forms of cancer pain. The most significant innovation in the treatment of inflammatory pain over the last years has been the introduction of selective cyclooxygenase inhibitors (COX-2 inhibitors). However, the efficacy of current COX-2 inhibitors is less substantial than first suggested, and the side effect profile causes concern. The treatment of inflammatory pain requires new therapeutic means with an improved side effect profile.
Migraine-associated pain attacks affect about 10 to 20% of the middle European population. Pain attacks are believed to originate from the sensitization of meningeal nociceptors by neuropeptides and/or their excitation by dilated meningeal blood vessels. At present migraine pain is usually treated with cyclooxygenase inhibitors and 5-hydroxytryptamine (serotonin) agonists (so called triptans). Pain relief is often unsatisfactory and treatment with both groups of agents bares significant gastrointestinal and cardiovascular risks.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA receptors are heteromeric, and are divided into three main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily; and (3) GABAC receptors, also members of the ligand-gated ion channel superfamily, but their distribution is confined to the retina. Benzodiazepine receptor ligands do not bind to GABAB and GABAC receptors. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to 21 including α, β, and γ subunits (6α, 4β, 4γ, 1δ, 1ε, 1π, 1θ, and 3ρ).
A characteristic property of GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) site. The benzodiazepine binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which benzodiazepine-based anxiolytic drugs exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BENZODIAZEPINE1 and BENZODIAZEPINE2, on the basis of radioligand binding studies on synaptosomal rat membranes. The BENZODIAZEPINE1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the α1 subunit in combination with a β subunit and γ2. It has been indicated that an α subunit, a β subunit and a γ subunit constitute the minimum requirement for forming a functional GABAA receptor.
Receptor subtype assemblies for BZ-sensitive GABAA receptors include amongst others the subunit combinations α1β2g2, α2β2,3g2, α3β2,3g2, α2βg3, and α5β3g2,3. Subtype assemblies containing an α1 subunit (α1β2γ2) are present in most areas of the brain and are thought to account for 40-50% of GABAA receptors in the rat. Subtype assemblies containing α2 and α3 subunits respectively are thought to account for about 25% and 17% GABAA receptors in the rat. Subtype assemblies containing an α5 subunit (α5β3γ2) are expressed predominately in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat. Two other major populations are the α2β2/3γ2 and α3β2/3γ2/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor population. Pharmacologically this combination appears to be equivalent to the BENZODIAZEPINE2 subtype as defined previously by radioligand binding, although the BENZODIAZEPINE2 subtype may also include certain α5-containing subtype assemblies.
The present pharmacology of agonists acting at the BZ site of GABAA receptors suggests that al containing receptors mediate sedation, anticonvulsant activity and anterograde amnesia, while α2 and/or α3 GABAA receptors mediate anxiolytic activity. The α5 containing GABAA receptors are involved in memory functions (U. Rudolph et al., Nature 1999, 401, 796; K. Löw et al., Science 2000, 290, 131; McKernan Nature Neurosci. 2000, 3, 587; F. Crestani et al., Proc. Nat. Acad. Sci. USA 2002, 99, 8980; M.S. Chambers et al., J. Med. Chem. 2003, 46, 2227).
The demonstration of the pharmacology of GABAA receptor subtypes has been achieved in vitro by studying ligand induced currents in oocytes that express mRNA for specific GABAA receptor subunits, or in vivo, by studying mice in which either the α1, α2, α3 or a 5 GABAA receptor is rendered diazepam-insensitive by a histidine to arginine point mutation, respectively α1(H101R), α2(H101R), α3(H126R), or α5(H105R). In the point-mutated mice the benzodiazepine pharmacology related to the respective receptor is absent as compared to wild type mice. In the following, the point mutated mouse mutants are referred to as GABAA receptor mutant mice, receptor mutant mice or mutant mice.
It is believed that agents acting selectively as benzodiazepine agonists at GABAA/α2, GABAA/α3, and/or GABAA/α5 receptors, possess desirable properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as benzodiazepine agonists are referred to hereinafter as “GABAA receptor agonists.” The GABAA/α1-selective (α1β2γ2) agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BENZODIAZEPINE1 binding site is mediated through GABAA receptors containing the α1 subunit.
There have been suggestions that some compounds that are selectively GABAA/α2 and/or GABAA/α3 receptor agonists rather than GABAA/α1 receptor agonists may be effective in the treatment of pain with a reduced propensity to cause sedation. An indication of this can be found in PCT published application WO2006061428, published Jun. 16, 2006, which discloses the use of are GABAA/α2, or GABAA/α3 receptor agonists including 1,2,4-triazolo[4,3-b]pyridazines, e.g. L-838,417, TPA 023 or CL-218,872, 1H-pyrido[3,4-b]indole derivatives, e.g. SL 651498, and pyrazolo[1,5-a]pyrimidines, e.g. ocinaplon, for the prevention and treatment of neuropathic, inflammatory and migraine associated pain. However, no disclosure was made of benzodiazepine derivatives that might be useful for the suppression, alleviation or prevention of neuropathic pain, migraine related pain and inflammatory pain.